2. Academic Validation
  3. Prostate cancer exploits BRD9-driven metabolic reprogramming to shape the aggressive phenotype

Prostate cancer exploits BRD9-driven metabolic reprogramming to shape the aggressive phenotype

  • Cell Death Dis. 2025 Apr 22;16(1):326. doi: 10.1038/s41419-025-07561-9.
Ye Lv 1,  Xinkai Mo 2,  Ruojia Zhang 3,  Yu Peng 4,  Tingting Feng 3 5,  Yuang Zhang 3 5,  Guanhua Song 6,  Luna Ge 3 5,  Yu Liu 3,  Guiwen Yang 7,  Lin Wang 8 9
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China.
  • 2 Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 3 Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 4 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 5 Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
  • 6 Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 7 Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China. yanggw@sdnu.edu.cn.
  • 8 Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. linwang@sdfmu.edu.cn.
  • 9 Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China. linwang@sdfmu.edu.cn.
PMID: 40263302 DOI: 10.1038/s41419-025-07561-9
Abstract

The aggressive phenotype of prostate Cancer (PCa) requires adaptation to androgen deprivation (AD) to progress into castration-resistant PCa (CRPC), including adaptation to AD-induced oxidative stress. However, our understanding of the oncogenes that maintain the redox balance during CRPC progression is limited. Here, we identified Bromodomain-containing protein 9 (BRD9) as a metabolic checkpoint for reprogramming cell metabolism to support tumor growth and impart a castration-resistant phenotype under metabolic and oxidative stress. Following oxidation, BRD9 recruited the nuclear transcription factor-Y A-subunit (NFYA) to induce glycogen Phosphorylase L (PYGL) expression, which directed glucose utilization through the pentose phosphate pathway, generating NADPH, and promoting clearance of Reactive Oxygen Species (ROS), thus maintaining redox balance. By disturbing redox homeostasis, BRD9 inhibition exerted oxidative pressure on PCa cells, sensitizing them to radiotherapy. This work identified BRD9 as a novel component in antioxidant reprogramming and indicates BRD9 targeting as a promising treatment strategy for PCa therapy.

Figures
Products